Clinical Edge

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Genotype may affect lifestyle’s influence on dementia risk

Key clinical point: Among older adults with low and intermediate genetic risk for dementia, favorable modifiable health and lifestyle factors are associated with lower likelihood of dementia. But among people at high genetic risk for dementia, these potentially modifiable factors may not have protective associations.

Major finding: Compared with participants with protective modifiable risk profiles, participants with unfavorable modifiable risk profiles had greater risk for dementia in a low–genetic risk group (hazard ratio, 2.51) and intermediate–genetic risk group (HR, 1.39), but not in a high–genetic risk group.

Study details: An analysis of long-term data on genetic and modifiable risk factors from 6,352 people aged 55 years and older in the population-based Rotterdam Study.

Disclosures: The Rotterdam Study is funded by Erasmus Medical Center and University, as well as a variety of Dutch organizations, institutes, and government ministries, and the European Commission. The authors had no competing interests.


Licher S et al. Nat Med. 2019 Aug 26. doi: 10.1038/s41591-019-0547-7.


The study by Dr. Licher and associates shows a clinically significant impact of a healthy lifestyle in reducing dementia. But what is surprising is that the effect was not seen in genetically higher-risk people.

About half of patients with dementia are apolipoprotein E epsilon-4 allele (APOE4) carriers, meaning half are not. Of those, most patients have a genotype with two APOE3 alleles, which is shared by the largest proportion of the human race. So, having a protective lifestyle could have a big public health impact if people comply with it.

If anything, the results strengthen our recommendations to people interested in lowering their risk for dementia with lifestyle modification. Bear in mind that APOE testing is not done routinely, so the vast majority of our patients do not know their APOE genotype. Since a healthy lifestyle can benefit the majority of the population (around 75%), even if it is less or ineffective in the APOE4 carrier group (about 25% of the population), it is certainly something to recommend. Of course, health care professionals already recommend heart healthy habits, which have an equivalent benefit, and sadly, adherence is relatively low. Adding that lifestyle modification may help prevent dementia might improve patient compliance. Starting healthy lifestyles as early in life as possible may be the key. It is less effective if we wait until we already have memory loss.

Finally, the study results regard relative risk, a concept that many fail to fully grasp. A person can still get dementia in any of the categories, including the “best one” (low genetic and lifestyle risk). It’s a matter of the odds being better or worse, but there is no guarantee of a positive or negative outcome.

Richard J. Caselli, MD, is professor of neurology at the Mayo Clinic Arizona in Scottsdale and associate director and clinical core director of the Arizona Alzheimer’s Disease Center, Phoenix. He made these comments in an interview.